chr10-87190552-G-T

Variant names:

• chr10-87190552-G-T
• rs373996048
• NM_001330112.2:c.2584G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001330112.2(SHLD2):​c.2584G>T​(p.Ala862Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A862T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SHLD2 NM_001330112.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.587
• Publications: 0 publications found

Genes affected

SHLD2 (HGNC:28773): (shieldin complex subunit 2) Involved in negative regulation of double-strand break repair via homologous recombination; positive regulation of double-strand break repair via nonhomologous end joining; and positive regulation of isotype switching. Located in nucleus and site of double-strand break. [provided by Alliance of Genome Resources, Apr 2022]

NUTM2A-AS1 (HGNC:45161): (NUTM2A antisense RNA 1)

LOC105378410 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11857).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330112.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHLD2	NM_001330112.2	MANE Select	c.2584G>T	p.Ala862Ser	missense	Exon 10 of 10	NP_001317041.1	Q86V20-2
	SHLD2	NM_001377161.1		c.2533G>T	p.Ala845Ser	missense	Exon 10 of 10	NP_001364090.1
	SHLD2	NM_001377160.1		c.2521G>T	p.Ala841Ser	missense	Exon 10 of 10	NP_001364089.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHLD2	ENST00000298786.5	TSL:5 MANE Select	c.2584G>T	p.Ala862Ser	missense	Exon 10 of 10	ENSP00000298786.3	Q86V20-2
	SHLD2	ENST00000898042.1		c.2728G>T	p.Ala910Ser	missense	Exon 12 of 12	ENSP00000568101.1
	SHLD2	ENST00000898054.1		c.2728G>T	p.Ala910Ser	missense	Exon 11 of 11	ENSP00000568113.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459654 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726146

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111788

Other (OTH) AF: 0.00 AC: 0 AN: 60204

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.58
DANN	Benign	0.37
DEOGEN2	Benign	0.0067	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.59
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.013
Sift	Benign	0.51	T
Sift4G	Benign	0.44	T
Polyphen		0.0020	B
Vest4		0.066
MutPred		0.29		Gain of relative solvent accessibility (P = 0.0082)
MVP		0.41
MPC		0.48
ClinPred		0.057	T
GERP RS		2.6
Varity_R		0.027
gMVP		0.18
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs373996048; hg19: chr10-88950309;